The Genetic Deconstruction of Psychosis

Department of Psychological Medicine, The School of Medicine, Cardiff University, Cardiff, UK.
Schizophrenia Bulletin (Impact Factor: 8.45). 08/2007; 33(4):905-11. DOI: 10.1093/schbul/sbm053
Source: PubMed


Psychiatric research, including the search for predisposing genes, has tended to proceed under the assumptions that schizophrenia and bipolar disorder, as defined in Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and International Statistical Classification of Diseases, 10th Revision, are discrete disease entities with distinct etiology and pathogenesis and that these disease entities can be identified by current "operational" diagnostic conventions. However, recent findings emerging from genetic studies show increasing evidence for an overlap in genetic susceptibility across the traditional binary classification of psychosis. Moreover, the emerging evidence suggests the possibility of relatively specific relationships between genotype and psychopathology. For example, variation in Disrupted in Schizophrenia 1 (DISC1) and Neuregulin 1 (NRG1) may confer susceptibility to a form of illness with mixed features of schizophrenia and mania. The elucidation of genotype-phenotype relationships is at an early stage, but current findings highlight the need to consider alternative approaches to classification and conceptualization for psychiatric research rather than continuing to rely heavily on the traditional categorical approach. We can expect that, over the coming years, molecular genetics will catalyze a reappraisal of psychiatric nosology as well as contribute in a major way to our understanding of pathophysiology and to the development of improved treatments. However, our understanding of the brain mechanisms that link specific gene actions and products to the subjective experience of psychopathological symptoms is likely to be bridged by employing intermediate (or endo-) phenotypes in the domains such as cognition, neurophysiology, or neuroanatomy rather than relying upon clinical measures alone.

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    • "Authors of the Diagnostic and Statistical Manual, 5th Edition (DSM-V) emphasise the importance of dimensional assessment of psychopathology (Heckers et al., 2013). The limitations of a categorical approach to diagnosis are well recognised: diagnostic groups have significant overlap in their clinical presentation, management strategies, prognosis, genetic underpinnings and clinical course (Kamphuis and Noordhof, 2009; Owen et al., 2007; Whitty et al., 2005; Bromet et al., 2011; Van et al., 2009). To date most FTD research has investigated only those diagnosed with schizophrenia, often drawing from hospital and institutional samples (Taylor et al., 1994; Berenbaum et al., 1985; Mortimer et al., 1990). "
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    ABSTRACT: Formal thought disorder (FTD) is a core feature of psychosis, however there are gaps in our knowledge about its prevalence and factor structure. We had two aims: first, to establish the factor structure of FTD; second, to explore the clinical utility of dimensions of FTD in order to further the understanding of its nosology. A cross-validation study was undertaken to establish the factor structure of FTD in first episode psychosis (FEP). The relative utility of FTD categories vs. dimensions across diagnostic categories was investigated. The prevalence of clinically significant FTD in this FEP sample was 21%, although 41% showed evidence of disorganised speech, 20% displayed verbosity and 24% displayed impoverished speech. A 3-factor model was identified as the best fit for FTD, with disorganisation, poverty and verbosity dimensions (GFI=0.99, RMR=0.07). These dimensions of FTD accurately distinguished affective from non-affective diagnostic categories. A categorical approach to FTD assessment was useful in identifying markers of clinical acuteness, as identified by short duration of untreated psychosis (OR=2.94, P<0.01) and inpatient treatment status (OR=3.98, P<0.01). FTD is moderately prevalent and multi-dimensional in FEP. Employing both a dimensional and categorical assessment of FTD gives valuable clinical information, however there may be a need to revise our conceptualisation of the nosology of FTD. The prognostic value of FTD, as well as its neural basis, requires elucidation. Copyright © 2015 Elsevier B.V. All rights reserved.
    Schizophrenia Research 08/2015; 168(1). DOI:10.1016/j.schres.2015.07.049 · 3.92 Impact Factor
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    • "a genetic risk at the level of endophenotypes or brain circuitry that underlies a number of major mental disorders. Indeed, at the genetic level, risk variants shared between multiple psychiatric disorders, such as schizophrenia, bipolar disorder, and autism, have been identified (Owen et al., 2007, 2011; Cuthbert & Insel, 2010). Important processes from where endophenotypes spanning a range of psychiatric disease might arise include the initial development of the nervous system and its subsequent refinement in the early years of life, and the functionality of synaptic connections within the circuits of the CNS. "
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    ABSTRACT: The disrupted in schizophrenia 1 (DISC1) gene is found at the breakpoint of an inherited chromosomal translocation, and segregates with major mental illnesses. Its potential role in central nervous system (CNS) malfunction has triggered intensive investigation of the biological roles played by DISC1, with the hope that this may shed new light on the pathobiology of psychiatric disease. Such work has ranged from investigations of animal behavior to detailed molecular-level analysis of the assemblies that DISC1 forms with other proteins. Here, we discuss the evidence for a role of DISC1 in synaptic function in the mammalian CNS.
    European Journal of Neuroscience 04/2014; 39(7). DOI:10.1111/ejn.12500 · 3.18 Impact Factor
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    • "Classically, psychotic disorders have been associated with functional changes in dopamine receptors of the striatum and limbic system [38]. However, more recent evidence points to a hypothesis of overlap between phenotypes characterized by schizophrenia-like symptoms more or less prominent in the clinical picture (spectral combinations of symptoms of bipolar disorder and prototypical schizophrenia), as well as overlapping effects of several susceptibility genes influencing these phenotypes [39]. Moreover, the 5-HT1A receptor has attracted particular interest as a potential target for enhancing cognition in patients with schizophrenia. "
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    ABSTRACT: Psychiatric comorbidities are frequent in temporal lobe epilepsy (TLE). It is plausible that variance in serotonin related genes is involved in the susceptibility of these associations.We report here the results on the association of tryptophan hydroxylase 2 (TPH2) gene polymorphisms with psychiatric comorbidities in TLE. A cohort study was conducted on 163 patients with TLE. We assessed the influence of the rs4570625 and rs17110747 polymorphisms in the TPH2 gene on psychiatric comorbidities in TLE. In patients with TLE, the presence of the T allele in the rs4570625 polymorphism was associated with psychotic disorders (OR=6.28; 95% CI=1.27–17.54; p=0.02), while the presence of the A allele in the rs17110747 polymorphism was associated with alcohol abuse (OR = 20.33; 95% CI = 1.60–258.46; p = 0.02). Moreover, we identified male gender (OR = 11.24; 95% CI=1.68–76.92; p=0.01) and family history of psychiatric disorder (OR=15.87; 95% CI=2.46–100; p=0.004) as factors also associated with alcohol abuse in TLE. Conversely, a family history of epilepsy was inversely associated with alcohol abuse (OR=0.03; 95% CI=0.001–0.60; p=0.02). Tryptophan hydroxylase 2 gene allele variants might be risk factors for psychiatric conditions in TLE. More specifically, we observed that the T allele in the rs4570625 polymorphism was associated with psychotic disorders, and the A allele in the rs17110747 TPH2 polymorphism was associated with alcohol abuse in patients with TLE. We believe that this study may open new research venues on the influence of the serotonergic system associated with psychiatric comorbidities in epilepsy.
    Epilepsy & Behavior 02/2014; 32:59-63. DOI:10.1016/j.yebeh.2014.01.007 · 2.26 Impact Factor
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